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Published on: March 11, 2020
Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse
Julie C Savage1, Marie-Kim St-Pierre2, Micaël Carrier2
1Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705, Boulevard Laurier, T2-50, Québec, QC, G1V 4G2, Canada. julie.savage@gmail.com.
Insights
Microglia in Huntington's disease (HD) mice show altered maturation and increased phagocytosis early on. These brain immune cells also exhibit reduced synaptic contact and altered synapse location, suggesting a role in HD pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the Huntingtin gene.
- While the genetic cause is known, the specific neuronal vulnerability and the role of microglia in HD remain unclear.
- Microglia, the brain's resident immune cells, are increasingly recognized for their involvement in neurodegenerative processes.
Purpose of the Study:
- To investigate the maturation and function of striatal microglia in a mouse model of Huntington's disease.
- To examine microglial morphology, phagocytic capacity, and synaptic interactions in relation to HD progression.
Main Methods:
- Utilized the R6/2 transgenic mouse model of HD, characterized by CAG repeat expansion and motor deficits.
- Employed light microscopy, transmission electron microscopy, and focused ion beam scanning electron microscopy to analyze microglial features and synaptic structures.
- Assessed microglial morphology, phagocytosis, and contacts with synapses at various ages (3, 10, and 13 weeks) in R6/2 and wild-type (WT) mice.
Main Results:
- In R6/2 mice, microglia exhibited a more mature phenotype and increased phagocytic activity even before the onset of motor deficits.
- Microglial processes in R6/2 mice showed reduced contact with synapses at later time points compared to younger R6/2 mice and age-matched WT controls.
- Synaptic density remained unaffected by genotype at 3 weeks but increased with maturation in WT mice; however, synapse location shifted from dendritic spines to trunks in R6/2 mice.
Conclusions:
- Microglia display early alterations in maturation and function in the context of Huntington's disease.
- These findings indicate that microglia are closely involved in the synaptic alterations and loss observed during HD pathogenesis.
- The study highlights microglia as potential therapeutic targets for mitigating synaptic dysfunction in HD.
Background:
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain's resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD.
Methods:
To provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10, and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam scanning electron microscopy.
Results:
At 3 weeks of age, prior to any known motor deficits, microglia in R6/2 animals displayed a more mature morphological phenotype than WT animals. Microglia from R6/2 mice across all ages also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week-old R6/2 mice made fewer contacts with synaptic structures than microglial processes in 3-week-old R6/2 mice and age-matched WT littermates. Synaptic density was not affected by genotype at 3 weeks of age but increased with maturation in WT mice. The location of synapses was lastly modified in R6/2 mice compared with WT controls, from targeting dendritic spines to dendritic trunks at both 3 and 10 weeks of age.
Conclusions:
These findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.
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